The prevalence of obesity is increasing at alarming rates in the United States such that bariatric surgery has become an accepted therapeutic option for adults and adolescents with morbid obesity. Bariatric surgery provides significant metabolic benefits, including resolution of type-2 diabetes and marked reduction in hypercholesterolemia, that precede the weight loss produced by these surgeries. The mechanisms responsible for these weight-independent metabolic benefits are poorly understood. Dr. Kohli's long-term research objective is to characterize the mechanisms behind these weight-loss-independent metabolic benefits of bariatric surgical procedures and translate those observations into more scalable non-invasive therapeutic measures. In this proposal Dr. Kohli will focus on the benefits of bariatric surgery to obesity related hypercholesterolemias by using a unique surgical procedure called "Ileal Transposition" in a rat model. This weight loss surgery has been previously shown to produce improved glucose tolerance similar to roux-en-y- gastric bypass without gastric size restriction or malabsorption. Dr. Kohli has generated exciting preliminary data using this surgical model that include a significant reduction in cholesterol levels that is independent of weight loss. The specific aims of his proposal will examine the mechanistic links between bile acid entero-hepatic circulation and cholesterol absorption, sensing, and endogenous production in this bariatric surgery model. He will also investigate the role of adaptation of the transposed segment of the ileum in reduction of cholesterol. These studies build on Dr. Kohli's prior work as a fellow investigating the mechanisms involved in lipid-induced nutritional stress producing hepatic steatosis. The primary goal of this mentored career development award is to provide a pathway for Dr. Kohli, a trained pediatric gastroenterologist and hepatologist, to achieve scientific independence. By developing an expertise in lipid and bile acid metabolism using small-animal surgical-obesity-intervention models, he will distinguish himself from his mentor, Professor Randy Seeley, and be well-positioned to make significant scientific and medical contributions to the understanding of obesity in children and adolescents. PUBLIC HEALTH RELEVANCE: Bariatric surgery is now an accepted treatment for the morbidly obese adult or adolescent. Certain benefits of these surgeries, such as reduced cholesterol and resolution of diabetes, occur even prior to weight loss. This proposal seeks to identify the key mechanisms involved in these weight-loss-independent improvements in cholesterol levels and then translate those findings to non-invasive more scalable treatment options.